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CNS Drugs

, Volume 19, Issue 4, pp 275–293 | Cite as

Substance P Receptor Antagonists in Psychiatry

Rationale for Development and Therapeutic Potential
  • Inga Herpfer
  • Klaus LiebEmail author
Leading Article

Abstract

Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects.

Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are — at least partially — distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant.

There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.

Keywords

Anxiety Disorder Paroxetine Depressed Patient Aprepitant Hippocampal Neurogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Inga Herpfer is a research fellow of the ‘Deutsche Forschungsgemeinschaft’ (DGF). Klaus Lieb received a grant from Merck Sharp & Dohme to study basic aspects of NK-1-receptor antagonists.

References

  1. 1.
    Murray CJL, Lopez AD, editors. Summary: the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Published by the Harvard School of Public Health on behalf of the World Health Organization and the World Bank. Cambridge, MA: Harvard University Press, 1996Google Scholar
  2. 2.
    Holsboer F. The role of peptides in treatment of psychiatric disorders. J Neural Transm Suppl 2003; 64: 17–34PubMedGoogle Scholar
  3. 3.
    Von Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol (Lond) 1931; 72: 74–87Google Scholar
  4. 4.
    Chang MM, Leeman SE, Niall HD. Amino acid sequence of substance P. Nat New Biol 1971; 232: 86–7PubMedCrossRefGoogle Scholar
  5. 5.
    Duffy RA, Hedrick JA, Randolph G, et al. Centrally administered hemokinin-1 (HK-1), a neurokinin NK1 receptor agonist, produces substance P-like behavioral effects in mice and gerbils. Neuropharmacology 2003; 45: 242–50PubMedCrossRefGoogle Scholar
  6. 6.
    Kurtz MM, Wang R, Clements MK, et al. Identification, localization and receptor characterization of novel mammalian substance P-like peptides. Gene 2002; 296: 205–12PubMedCrossRefGoogle Scholar
  7. 7.
    Krause JE, Chirgwin JM, Carter MS, et al. Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc Natl Acad Sci U S A 1987; 84: 881–5PubMedCrossRefGoogle Scholar
  8. 8.
    Harmar AJ, Hyde V, Chapman K. Identification and cDNA sequence of delta-preprotachykinin, a fourth splicing variant of the rat substance P precursor. FEBS Lett 1990; 275: 22–4PubMedCrossRefGoogle Scholar
  9. 9.
    Lai JP, Douglas SD, Rappaport E, et al. Identification of a delta isoform of preprotachykinin mRNA in human mononuclear phagocytes and lymphocytes. J Neuroimmunol 1998; 91: 121–8PubMedCrossRefGoogle Scholar
  10. 10.
    Kotani H, Hoshimaru M, Nawa H, et al. Structure and gene organization of bovine neuromedin K precursor. Proc Natl Acad Sci U S A 1986; 83: 7074–8PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang Y, Lu L, Furlonger C, et al. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat Immunol 2000; 1: 392–7PubMedCrossRefGoogle Scholar
  12. 12.
    Hökfelt T, Broberger C, Xu ZQ, et al. Neuropeptides: an overview. Neuropharmacology 2000; 39: 1337–56PubMedCrossRefGoogle Scholar
  13. 13.
    Pelletier G, Steinbusch HW, Verhofstad AA. Immunoreactive substance P and serotonin present in the same dense-core vesicles. Nature 1981; 293: 71–2PubMedCrossRefGoogle Scholar
  14. 14.
    Pickel VM, Joh TH, Reis DJ, et al. Electron microscopic localization of substance P and enkephalin in axon terminals related to dendrites of catecholaminergic neurons. Brain Res 1979; 160: 387–400PubMedCrossRefGoogle Scholar
  15. 15.
    Thureson-Klein A, Klein RL, Zhu PC. Exocytosis from large dense cored vesicles as a mechanism for neuropeptide release in the peripheral and central nervous system. Scan Electron Microsc 1986; (Pt 1): 179-87Google Scholar
  16. 16.
    Huang LYM, Neher E. Ca2+-dependent exocytosis in the somata of dorsal root ganglion neurons. Neuron 1996; 17: 135–45PubMedCrossRefGoogle Scholar
  17. 17.
    Regoli D, Boudon A, Fauchere JL. Receptors and antagonists for substance P and related peptides. Pharmacol Rev 1994; 46: 551–99PubMedGoogle Scholar
  18. 18.
    Gether U, Johansen TE, Snider RM, et al. Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Nature 1993; 362: 345–8PubMedCrossRefGoogle Scholar
  19. 19.
    Mantyh PW, Allen CJ, Ghilardi JR, et al. Rapid endocytosis of a G protein-coupled receptor: substance P evoked internalization of its receptor in the rat striatum in vivo. Proc Natl Acad Sci U S A 1995; 92: 2622–6PubMedCrossRefGoogle Scholar
  20. 20.
    Grady EF, Garland AM, Gamp PD, et al. Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor. Mol Biol Cell 1995; 6: 509–24PubMedGoogle Scholar
  21. 21.
    Smith DW, Hewson L, Fuller P, et al. The substance P antagonist L-760,735 inhibits stress-induced NK(1) receptor internalisation in the basolateral amygdala. Brain Research 1999; 848: 90–5PubMedCrossRefGoogle Scholar
  22. 22.
    Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281: 1640–5PubMedCrossRefGoogle Scholar
  23. 23.
    Takayama H, Ota Z, Ogawa N. Effect of immobilization stress on neuropeptides and their receptors in rat central nervous system. Regul Pept 1986 Oct; 15: 239–48PubMedCrossRefGoogle Scholar
  24. 24.
    Chubb IW, Hodgson AJ, White GH. Acetylcholinesterase hydrolyzes substance P. Neuroscience 1980; 5: 2065–72PubMedCrossRefGoogle Scholar
  25. 25.
    Persson S, Le Greves P, Thornwall M, et al. Neuropeptide converting and processing enzymes in the spinal cord and cerebrospinal fluid. Prog Brain Res 1995; 104: 111–30PubMedCrossRefGoogle Scholar
  26. 26.
    Mai JK, Stephens PH, Hopf A, et al. Substance P in the human brain. Neuroscience 1986; 17: 709–39PubMedCrossRefGoogle Scholar
  27. 27.
    Pioro EP, Mai JK, Cuello AC. Distribution of substance P and enkephalin immunoreactive neurons and fibers. In: Paxinos G, editor. The human nervous system. San Diego (CA): Academic Press, 1990: 1051–94Google Scholar
  28. 28.
    Nomura H, Shiosaka S, Tohyama M. Distribution of substance P-like immunoreactive structures in the brainstem of the adult human brain: an immunocytochemical study. Brain Res 1987; 404: 365–70PubMedCrossRefGoogle Scholar
  29. 29.
    Chawla MK, Gutierrez GM, Young III WS, et al. Localization of neurons expressing substance P and neurokinin B gene transcripts in the human hypothalamus and basal forebrain. J Comp Neurol 1997; 384: 429–42PubMedCrossRefGoogle Scholar
  30. 30.
    Feuerstein TJ, Gleichauf O, Landwehrmeyer GB. Modulation of cortical acetylcholine release by serotonin: the role of substance P interneurons. Naunyn Schmiedebergs Arch Pharmacol 1996; 354: 618–26PubMedGoogle Scholar
  31. 31.
    Battaglia G, Rustioni A. Coexistence of glutamate and substance P in dorsal root ganglion neurons of the rat and monkey. J Comp Neurol 1988; 277: 302–12PubMedCrossRefGoogle Scholar
  32. 32.
    De Biasi S, Rustioni A. Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord. Proc Natl Acad Sci U S A 1988; 85: 7820–4PubMedCrossRefGoogle Scholar
  33. 33.
    Hökfelt T, Millhorn D, Seroogy K, et al. Coexistence of peptides with classical neurotransmitters. Experientia 1987; 43(7): 768–80PubMedCrossRefGoogle Scholar
  34. 34.
    Sergeyev V, Hökfelt T, Hurd Y. Serotonin and substance P coexist in dorsal raphe neurons of the human brain. Neuroreport 1999; 10: 3967–70PubMedCrossRefGoogle Scholar
  35. 35.
    Nakaya Y, Kaneko T, Shigemoto R, et al. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J Comp Neurol 1994; 347: 249–74PubMedCrossRefGoogle Scholar
  36. 36.
    Mantyh PW. Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 2002; 63 Suppl. 11: 6–10Google Scholar
  37. 37.
    Dietl MM, Palacios JM. Phylogeny of tachykinin receptor localization in the vertebrate central nervous system: apparent absence of neurokinin-2 and neurokinin-3 binding sites in the human brain. Brain Res 1991; 539: 211–22PubMedCrossRefGoogle Scholar
  38. 38.
    Jordan D, Kermadi I, Rambaud C, et al. Regional distribution of substance P binding sites in the brainstem of the human newborn. Brain Res 1995; 695: 117–24PubMedCrossRefGoogle Scholar
  39. 39.
    Caberlotto L, Hurd YL, Murdock P, et al. Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain. Eur J Neurosci 2003; 17: 1736–46PubMedCrossRefGoogle Scholar
  40. 40.
    Tooney PA, Au GG, Chahl LA. Localisation of tachykinin NK1 and NK3 receptors in the human prefrontal and visual cortex. Neurosci Lett 2000; 283: 185–8PubMedCrossRefGoogle Scholar
  41. 41.
    Chen LW, Wei LC, Liu HL, et al. Noradrenergic neurons expressing substance P receptor (NK1) in the locus coeruleus complex: a double immunofluorescence study in the rat. Brain Res 2000; 873: 155–9PubMedCrossRefGoogle Scholar
  42. 42.
    Ma QP, Bleasdale C. Modulation of brain stem monoamines and gamma-aminobutyric acid by NK1 receptors in rats. Neuroreport 2002; 13: 1809–12PubMedCrossRefGoogle Scholar
  43. 43.
    Commons KG, Valentino RJ. Cellular basis for the effects of substance P in the periaqueductal grey and dorsal raphe nucleus. J Comp Neurol 2002; 447: 82–97PubMedCrossRefGoogle Scholar
  44. 44.
    Bartho L, Holzer P. Search for a physiological role of substance P in gastrointestinal motility. Neuroscience 1985; 16: 1–32PubMedCrossRefGoogle Scholar
  45. 45.
    Greeno EW, Mantyh P, Vercellotti GM, et al. Functional neurokinin 1 receptors for substance P are expressed by human vascular endothelium. J Exp Med 1993; 177: 1269–76PubMedCrossRefGoogle Scholar
  46. 46.
    Maggi CA. The effects of tachykinins on inflammatory and immune cells. Regul Pept 1997; 70: 75–90PubMedCrossRefGoogle Scholar
  47. 47.
    Herrero JF, Laird JM, Lopez-Garcia JA. Wind-up of spinal cord neurons and pain sensation: much ado about something? Prog Neurobiol 2000; 61: 169–203PubMedCrossRefGoogle Scholar
  48. 48.
    Quartara L, Maggi CA. The tachykinin NK1 receptor. Part II: distribution and pathophysiological roles. Neuropeptides 1998; 32: 1–49Google Scholar
  49. 49.
    Nilsson J, von Euler AM, Dalsgaard CJ. Stimulation of connective tissue cell growth by substance P and substance K. Nature 1985; 315: 61–3PubMedCrossRefGoogle Scholar
  50. 50.
    Iwasaki Y, Kinoshita M, Ikseda K, et al. Trophic effect of various neuropeptides on the cultured ventral spinal cord of rat embryo. Neurosci Lett 1989; 101: 316–20PubMedCrossRefGoogle Scholar
  51. 51.
    De Felipe C, Pinnock RD, Hunt SP. Modulation of chemotropism in the developing spinal cord by substance P. Science 1995; 267: 899–902PubMedCrossRefGoogle Scholar
  52. 52.
    Lieb K, Fiebich BL, Busse-Grawitz M, et al. Effects of substance P and selected other neuropeptides on the synthesis of interleukin-1 beta and interleukin-6 in human monocytes: a re-examination. J Neuroimmunol 1996; 67: 77–81PubMedGoogle Scholar
  53. 53.
    Lieb K, Fiebich BL, Berger M, et al. The neuropeptide substance P activates transcription factor NF-kappaB and kappaB-dependent gene expression in human astrocytoma cells. J Immunol 1997; 159: 4952–8PubMedGoogle Scholar
  54. 54.
    Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 2002; 302: 839–45PubMedCrossRefGoogle Scholar
  55. 55.
    Barker R. Substance P and neurodegenerative disorders: a speculative review. Neuropeptides 1991; 20: 73–8PubMedCrossRefGoogle Scholar
  56. 56.
    Rupniak NMJ, Kramer MS. Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol Sci 1999; 20: 485–90PubMedCrossRefGoogle Scholar
  57. 57.
    Herpfer I, Lieb K. Substance P and substance P receptor antagonists in the pathogenesis and treatment of affective disorders. World J Biol Psychiatry 2003; 4: 56–63PubMedCrossRefGoogle Scholar
  58. 58.
    Rupniak NMJ. Elucidating the antidepressant actions of substance P (NK1 receptor) antagonists. Curr Opin Investig Drugs 2002; 3: 257–61PubMedGoogle Scholar
  59. 59.
    Bannon MJ, Deutch AY, Tam SY, et al. Mild footshock stress dissociates substance P from substance K and dynorphin from Met- and Leu-enkephalin. Brain Res 1986 Sep 3; 381: 393–6PubMedCrossRefGoogle Scholar
  60. 60.
    Lisoprawski A, Blanc G, Glowinski J. Activation by stress of the habenulo-interpeduncular substance P neurons in the rat. Neurosci Lett 1981 Aug 7; 25: 47–51PubMedCrossRefGoogle Scholar
  61. 61.
    Siegel RA, Düker EM, Fuchs E, et al. Responsiveness of mesolimbic, mesocortical, septal and hippocampal cholecystokinin and substance P neuronal systems to stress, in the male rat. Neurochem Int 1984; 6: 783–9PubMedCrossRefGoogle Scholar
  62. 62.
    Siegel RA, Duker EM, Pahnke U, et al. Stress-induced changes in cholecystokinin and substance P concentrations in discrete regions of the rat hypothalamus. Neuroendocrinology 1987 Jun; 46: 75–81PubMedCrossRefGoogle Scholar
  63. 63.
    Nakamura H, Moroji T, Nohara S, et al. Effects of whole-body vibration stress on substance P- and neurotensin-like immunoreactivity in the rat brain. Environ Res 1990 Aug; 52: 155–63PubMedCrossRefGoogle Scholar
  64. 64.
    Brodin E, Rosen A, Schott E, et al. Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions. Neuropeptides 1994 Apr; 26: 253–60PubMedCrossRefGoogle Scholar
  65. 65.
    Rosen A, Brodin K, Eneroth P, et al. Short-term restraint stress and s.c. saline injection alter the tissue levels of substance P and cholecystokinin in the peri-aqueductal grey and limbic regions of rat brain. Acta Physiol Scand 1992 Nov; 146: 341–8Google Scholar
  66. 66.
    Chowdrey HS, Larsen PJ, Harbuz MS, et al. Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress. Life Sci 1995; 57: 2021–9PubMedCrossRefGoogle Scholar
  67. 67.
    Allen BJ, Rogers SD, Ghilardi JR, et al. Noxious cutaneous thermal stimuli induce a graded release of endogenous substance P in the spinal cord: imaging peptide action in vivo. J Neurosci 1997; 17: 5921–7PubMedGoogle Scholar
  68. 68.
    Vaupel R, Jarry H, Schlomer HT, et al. Differential response of substance P-containing subtypes of adrenomedullary cells to different stressors. Endocrinology 1988; 123: 2140–5PubMedCrossRefGoogle Scholar
  69. 69.
    Ebner K, Rupniak NM, Saria A, et al. Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci U S A 2004; 101: 4280–5PubMedCrossRefGoogle Scholar
  70. 70.
    Elliott PJ. Place aversion induced by the substance P analogue, dimethyl-C7, is not state dependent: implication of substance P in aversion. Exp Brain Research 1988; 73: 354–6Google Scholar
  71. 71.
    Aguiar MS, Brandão ML. Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal grey on the behaviour of rats in the plus-maze test. Physiol Behavior 1996; 60: 1183–6CrossRefGoogle Scholar
  72. 72.
    Aguiar MS, Brandão ML. Conditioned place aversion produced by microinjections of substance P into the periaqueductal grey of rats. Behav Pharmacol 1994; 5: 369–73PubMedCrossRefGoogle Scholar
  73. 73.
    Gavioli EC, Canteras NS, De Lima TC. Anxiogenic-like effect induced by substance P injected into the lateral septal nucleus. Neuroreport 1999; 10: 3399–403PubMedCrossRefGoogle Scholar
  74. 74.
    Teixeira RM, Santos AR, Ribeiro SJ, et al. Effects of central administration of tachykinin receptor agonists and antagonists on plus-maze behavior in mice. Eur J Pharmacol 1996; 311: 7–14PubMedCrossRefGoogle Scholar
  75. 75.
    Krase W, Koch M, Schnitzler HU. Substance P is involved in the sensitization of the acoustic startle response by footshocks in rats. Behav Brain Res 1994; 63: 81–8PubMedCrossRefGoogle Scholar
  76. 76.
    Brent PJ, Johnston PA, Chahl LA. Increased plasma catecholamines and locomotor activity induced by centrally administered substance P in guinea-pigs. Neuropharmacology 1988; 27: 743–8PubMedCrossRefGoogle Scholar
  77. 77.
    Piot O, Betschart J, Grall I, et al. Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea-pig. Brit J Pharmacol 1995; 116: 2496–502CrossRefGoogle Scholar
  78. 78.
    Bristow LJ, Young L. Chromodacryorrhea and repetitive hind paw tapping: models of peripheral and central tachykinin NK1 receptor activation in gerbils. Eur J Pharmacol 1994; 253: 245–52PubMedCrossRefGoogle Scholar
  79. 79.
    Van Wimersma Greidanus TB, Maigret C. Grooming behavior induced by substance P. Eur J Pharmacol 1988; 154: 217–20PubMedCrossRefGoogle Scholar
  80. 80.
    Katz RJ. Central injection of substance P elicits grooming behavior and motor inhibition in mice. Neurosci Lett 1979; 12: 133–6PubMedCrossRefGoogle Scholar
  81. 81.
    Gradin K, Qadri F, Nomikos GG, et al. Substance P injection into the dorsal raphe increases blood pressure and serotonin release in hippocampus of conscious rats. Eur J Pharmacol 1992; 218: 363–7PubMedCrossRefGoogle Scholar
  82. 82.
    Unger T, Carolus S, Demmert G, et al. Substance P induces a cardiovascular defense reaction in the rat: pharmacological characterization. Circ Res 1988; 63: 812–20PubMedCrossRefGoogle Scholar
  83. 83.
    Hasenöhrl RU, Gerhardt P, Huston JP. Positively reinforcing effects of the neurokinin substance P in the basal forebrain: mediation by its C-terminal sequence. Exp Neurol 1992; 115: 282–91PubMedCrossRefGoogle Scholar
  84. 84.
    Nikolaus S, Huston JP, Hasenöhrl RU. Reinforcing effects of neurokinin substance P in the ventral pallidum: mediation by the tachykinin NK1 receptor. Eur J Pharmacol 1999; 370: 93–9PubMedCrossRefGoogle Scholar
  85. 85.
    Hasenöhrl RU, Jentjens O, De Souza Silva MA, et al. Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region. Eur J Pharmacol 1998; 354: 123–33PubMedCrossRefGoogle Scholar
  86. 86.
    Bilkei-Gorzo A, Racz I, Michel K, et al. Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J Neurosci 2002 Nov 15; 22: 10046–52PubMedGoogle Scholar
  87. 87.
    Oblin A, Zivkovic B, Bartholini G. Involvement of the D-2 dopamine receptor in the neuroleptic-induced decrease in nigral substance P. Eur J Pharmacol 1984; 105: 175–7PubMedCrossRefGoogle Scholar
  88. 88.
    Brodin K, Ogren SO, Brodin E. Clomipramine and clonazepam increase cholecystokinin levels in rat ventral tegmental area and limbic regions. Eur J Pharmacol 1994; 263: 175–80PubMedCrossRefGoogle Scholar
  89. 89.
    Hamon M, Gozlan H, Bourgoin S, et al. Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline. Neuropharmacology 1987; 26: 531–9PubMedCrossRefGoogle Scholar
  90. 90.
    Brodin E, Ogren SO, Theodorsson-Norheim E. Effects of subchronic treatment with imipramine, zimelidine and alaproclate on regional tissue levels of substance P- and neurokinin A/ neurokinin B-like immunoreactivity in the brain and spinal cord of the rat. Neuropharmacology 1987; 26: 581–90PubMedCrossRefGoogle Scholar
  91. 91.
    Shirayama Y, Mitsushio H, Takashima M, et al. Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat. Brain Res 1996; 739: 70–8PubMedCrossRefGoogle Scholar
  92. 92.
    Rosen A, Franck J, Brodin E. Effects of acute systemic treatment with the 5 HT-uptake blocker alaproclate on tissue levels and release of substance P in rat periaqueductal grey. Neuropeptides 1995; 28: 317–24PubMedCrossRefGoogle Scholar
  93. 93.
    Walker PD, Riley LA, Hart RP, et al. Serotonin regulation of neostriatal tachykinins following neonatal 6-hydroxydopamine lesions. Brain Res 1991; 557: 31–6PubMedCrossRefGoogle Scholar
  94. 94.
    Riley LA, Jonakait GM, Hart RP. Serotonin modulates the levels of mRNAS coding for thyrotropin-releasing hormone and preprotachykinin by different mechanisms in medullary raphe neurons. Brain Res Mol Brain Res 1993; 17: 251–7PubMedCrossRefGoogle Scholar
  95. 95.
    Sartori SB, Burnet PW, Sharp T, et al. Evaluation of the effect of chronic antidepressant treatment on neurokinin-1 receptor expression in the rat brain. Neuropharmacology 2004; 46: 1177–83PubMedCrossRefGoogle Scholar
  96. 96.
    Rimon R, Le Greves P, Nyberg F, et al. Elevation of substance P-like peptides in the CSF of psychiatric patients. Biol Psychiatry 1984; 19: 509–16PubMedGoogle Scholar
  97. 97.
    Heikkila L, Rimon R, Terenius L. Dynorphin A and substance P in the cerebrospinal fluid of schizophrenic patients. Psychiatry Res 1990; 34: 229–36PubMedCrossRefGoogle Scholar
  98. 98.
    Berrettini WH, Rubinow DR, Nurnberger JIJ, et al. CSF substance P immunoreactivity in affective disorders. Biol Psychiatry 1985; 20: 965–70PubMedCrossRefGoogle Scholar
  99. 99.
    Toresson G, Brodin E, Wahlström A, et al. Detection of N-terminally extended substance P, but not of substance P in human cerebrospinal fluid — quantitation with HPLC-RIA. J Neurochem 1988; 50: 1701–7PubMedCrossRefGoogle Scholar
  100. 100.
    Martensson B, Nyberg S, Toresson G, et al. Fluoxetine treatment of depression. Acta Psychiatr Scand 1989; 79: 586–96PubMedCrossRefGoogle Scholar
  101. 101.
    Ackenheil M. Genetics and pathophysiology of affective disorders: relationship to fibromyalgia. Z Rheumatol 1998; 57 Suppl. 2: 5–7CrossRefGoogle Scholar
  102. 102.
    Russell IJ. The promise of substance P inhibitors in fibromyalgia. Rheum Dis Clin North Am 2002; 28: 329–42PubMedCrossRefGoogle Scholar
  103. 103.
    Schedlowski M, Fluge T, Richter S, et al. Beta-endorphin, but not substance-P, is increased by acute stress in humans. Psychoneuroendocrinology 1995; 20: 103–10PubMedCrossRefGoogle Scholar
  104. 104.
    Weiss DW, Hirt R, Tarcic N, et al. Studies in psychoneuroimmunology: psychological, immunological, and neuroendocrinological parameters in Israeli civilians during and after a period of Scud missile attacks. Behav Med 1996; 22: 5–14PubMedCrossRefGoogle Scholar
  105. 105.
    Bondy B, Baghai TC, Minov C, et al. Substance P serum levels are increased in major depression: preliminary results. Biol Psychiatry 2003; 53: 538–42PubMedCrossRefGoogle Scholar
  106. 106.
    Lieb K, Walden J, Grunze H, et al. Serum levels of substance P and response to antidepressant pharmacotherapy. Pharmacopsychiatry. In pressGoogle Scholar
  107. 107.
    Deuschle M, Sander P, Herpfer I, et al. Substance P in serum and cerebrospinal fluid of depressed patients: no effect of antidepressant treatment. Psychiatry Res. In pressGoogle Scholar
  108. 108.
    Freed AL, Audus KL, Lunte SM. Investigation of substance P transport across the blood-brain barrier. Peptides 2002; 23: 157–65PubMedCrossRefGoogle Scholar
  109. 109.
    Clark JW, Senanayake PD, Solomon GD, et al. Substance P: correlation of CSF and plasma levels. Headache 1994; 34: 261–4PubMedCrossRefGoogle Scholar
  110. 110.
    Chiodera P, Coiro V. Effects of intravenous infusion of substance P on arginine vasopressin and oxytocin secretion in normal men. Brain Res 1992; 569: 173–6PubMedCrossRefGoogle Scholar
  111. 111.
    Coiro V, Volpi R, Capretti L, et al. Intravenously infused substance P enhances basal and growth hormone (GH) releasing hormone-stimulated GH secretion in normal men. Peptides 1992; 13: 843–6PubMedCrossRefGoogle Scholar
  112. 112.
    Coiro V, Volpi R, Capretti L, et al. Luteinizing hormone response to an intravenous infusion of substance P in normal men. Metabolism 1992; 41: 689–91PubMedCrossRefGoogle Scholar
  113. 113.
    Coiro V, Volpi R, Capretti L, et al. Effect of substance P on basal and thyrotropin-releasing hormone-stimulated thyrotropin release in humans. Metabolism 1995; 44: 474–7PubMedCrossRefGoogle Scholar
  114. 114.
    Coiro V, Capretti L, Volpi R, et al. Stimulation of ACTH/ Cortisol by intravenously infused substance P in normal men: inhibition by sodium valproate. Neuroendocrinology 1992; 56: 459–63PubMedCrossRefGoogle Scholar
  115. 115.
    Lieb K, Ahlvers K, Dancker K, et al. Effects of the neuropeptide substance P on sleep, mood, and neuroendocrine measures in healthy young men. Neuropsychopharmacol 27; 2002: 1041-9Google Scholar
  116. 116.
    Burnet PW, Harrison PJ. Substance P (NK1) receptors in the cingulate cortex in unipolar and bipolar mood disorder and schizophrenia. Biol Psychiatry 2000; 47: 80–3PubMedCrossRefGoogle Scholar
  117. 117.
    Stockmeier CA, Shi X, Konick L, et al. Neurokinin-I receptors are decreased in major depressive disorder. Neuroreport 2002; 13: 1223–7PubMedCrossRefGoogle Scholar
  118. 118.
    Snider RM, Constantine JW, Lowe IJ, et al. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science 1991; 251: 435–7PubMedCrossRefGoogle Scholar
  119. 119.
    Snijdelaar DG, Dirksen R, Slappendel R, et al. Substance P. Eur J Pain 2000; 4: 121–35PubMedCrossRefGoogle Scholar
  120. 120.
    Hill R. NK1 (substance P) receptor antagonists — why are they not analgesic in humans? Trends Pharmacol Sci 2000; 21: 244–6PubMedCrossRefGoogle Scholar
  121. 121.
    Littman BH, Newton FA, Russell IJ. Substance P antagonism in fibromyalgia: a trial with CJ-11974. In: Abstracts from the World Conference on Pain; Seattle, WA: IASP Press, 1999: 67Google Scholar
  122. 122.
    Van Belle S, Lichinitser MR, Navari RM, et al. Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869. Cancer 2002; 94: 3032–41PubMedCrossRefGoogle Scholar
  123. 123.
    Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003; 91: 87–94PubMedCrossRefGoogle Scholar
  124. 124.
    Quartara L, Maggi CA. The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. Neuropeptides 1997; 31: 537–63Google Scholar
  125. 125.
    Conley RK, Cumberbatch MJ, Mason GS, et al. Substance P (neurokinin 1) receptor antagonists enhance dorsal raphe neuronal activity. J Neurosci 2002; 22: 7730–6PubMedGoogle Scholar
  126. 126.
    Maubach KA, Martin K, Chicchi G, et al. Chronic substance P (NK1) receptor antagonist and conventional antidepressant treatment increases burst firing of monoamine neurons in the locus coeruleus. Neuroscience 2002; 109: 609–17PubMedCrossRefGoogle Scholar
  127. 127.
    Bert L, Rodier D, Bougault I, et al. Permissive role of neurokinin NK(3) receptors in NK(1) receptor-mediated activation of the locus coeruleus revealed by SR 142801. Synapse 2002; 43: 62–9PubMedCrossRefGoogle Scholar
  128. 128.
    Haddjeri N, Blier P. Effect of neurokinin-I receptor antagonists on the function of 5-HT and noradrenaline neurons. Neuroreport 2000; 11: 1323–7PubMedCrossRefGoogle Scholar
  129. 129.
    Haddjeri N, Blier P. Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission. Biol Psychiatry 2001; 50: 191–9PubMedCrossRefGoogle Scholar
  130. 130.
    Millan MJ, Lejeune F, De Nanteuil G, et al. Selective blockade of neurokinin (NK)(1) receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats. J Neurochem 2001; 76: 1949–54PubMedCrossRefGoogle Scholar
  131. 131.
    Santarelli L, Gobbi G, Debs PC, et al. Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci U S A 2001; 98: 1912–7PubMedCrossRefGoogle Scholar
  132. 132.
    Froger N, Gardier AM, Moratalla R, et al. 5-hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P(neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization. J Neurosci 2001; 21: 8188–97PubMedGoogle Scholar
  133. 133.
    Zocchi A, Varnier G, Arban R, et al. Effects of antidepressant drugs and GR 205171, an neurokinin-1 (NK1) receptor antagonist, on the response in the forced swim test and on monoamine extracellular levels in the frontal cortex of the mouse. Neurosci Lett 2003; 345: 73–6PubMedCrossRefGoogle Scholar
  134. 134.
    Manev H, Uz T, Smalheiser NR, et al. Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol 2001; 411: 67–70PubMedCrossRefGoogle Scholar
  135. 135.
    Chen B, Dowlatshahi D, MacQueen GM, et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001; 50: 260–5PubMedCrossRefGoogle Scholar
  136. 136.
    Shirayama Y, Chen AC, Nakagawa S, et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002; 22: 3251–61PubMedGoogle Scholar
  137. 137.
    Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 2002; 82: 1367–75PubMedCrossRefGoogle Scholar
  138. 138.
    Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–9PubMedCrossRefGoogle Scholar
  139. 139.
    Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry 2000; 157: 115–8PubMedCrossRefGoogle Scholar
  140. 140.
    van Kampen M, Kramer M, Hiemke C, et al. The chronic psychosocial stress paradigm in male tree shrews: evaluation of a novel animal model for depressive disorders. Stress 2002; 5: 37–46PubMedCrossRefGoogle Scholar
  141. 141.
    Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 2001; 98: 12796–801PubMedCrossRefGoogle Scholar
  142. 142.
    van der Hart MG, Czeh B, de Biurrun G, et al. Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume. Mol Psychiatry 2002; 7: 933–41PubMedCrossRefGoogle Scholar
  143. 143.
    Morcuende S, Gadd CA, Peters M, et al. Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice. Eur J Neurosci 2003; 18: 1828–36PubMedCrossRefGoogle Scholar
  144. 144.
    Zernig G, Dietrich H, Maggi CA, et al. The substance P (NK1) receptor antagonist (+/−)-CP-96,345 causes sedation and motor impairment in Swiss albino mice in the black-and-white box behavioral paradigm. Neurosci Lett 1992; 143: 169–72PubMedCrossRefGoogle Scholar
  145. 145.
    Rupniak NM, Carlson EC, Harrison T, et al. Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology 2000; 39: 1413–21PubMedCrossRefGoogle Scholar
  146. 146.
    Boyce S, Smith D, Carlson E, et al. Intra-amygdala injection of the substance P [NK(1) receptor] antagonist L-760735 inhibits neonatal vocalisations in guinea-pigs. Neuropharmacology 2001; 41: 130–7PubMedCrossRefGoogle Scholar
  147. 147.
    Ballard TM, Sanger S, Higgins GA. Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist. Eur J Pharmacol 2001; 412: 255–64PubMedCrossRefGoogle Scholar
  148. 148.
    Rupniak NM, Webb JK, Fisher A, et al. The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils. Neuropharmacology 2003; 44: 516–23PubMedCrossRefGoogle Scholar
  149. 149.
    Rupniak NM, Carlson EJ, Webb JK, et al. Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 2001; 12: 497–508PubMedCrossRefGoogle Scholar
  150. 150.
    File SE. NKP608, an NK1 receptor antagonist, has an anxiolytic action in the social interaction test in rats. Psychopharmacology 2000; 152: 105–9PubMedCrossRefGoogle Scholar
  151. 151.
    Cheeta S, Tucci S, Sandhu J, et al. Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils. Brain Res 2001; 915: 170–5PubMedCrossRefGoogle Scholar
  152. 152.
    Gentsch C, Cutler M, Vassout A, et al. Anxiolytic effect of NKP608, a NKl-receptor antagonist, in the social investigation test in gerbils. Behav Brain Res 2002; 133: 363–8PubMedCrossRefGoogle Scholar
  153. 153.
    Gavioli EC, Canteras NS, De Lima TCM. The role of lateral septal NK1 receptors in mediating anxiogenic effects induced by intracerebroventricular injection of substance P. Behav Brain Res 2002; 134: 411–5PubMedCrossRefGoogle Scholar
  154. 154.
    Papp M, Vassout A, Gentsch C. The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats. Behav Brain Res 2000; 115: 19–23PubMedCrossRefGoogle Scholar
  155. 155.
    Teixeira RM, De Lima TC. Involvement of tachykinin NK1 receptor in the behavioral and immunological responses to swimming stress in mice. Neuropeptides 2003; 37: 307–15PubMedCrossRefGoogle Scholar
  156. 156.
    Varty GB, Cohen-Williams ME, Morgan CA, et al. The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists. Neuropsychopharmacology 2002; 27: 371–9PubMedCrossRefGoogle Scholar
  157. 157.
    Shaikh MB, Steinberg A, Siegel A. Evidence that substance P is utilized in medial amygdaloid facilitation of defensive rage behavior in the cat. Brain Res 1993; 625: 283–94PubMedCrossRefGoogle Scholar
  158. 158.
    De Felipe C, Herrero JF, O’Brien JA, et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 1998; 392: 394–7PubMedCrossRefGoogle Scholar
  159. 159.
    Santarelli L, Gobbi G, Blier P, et al. Behavioral and physiologic effects of genetic or pharmacologic inactivation of the substance P receptor (NK1). J Clin Psychiatry 2002; 63Suppl. 11: 11–7PubMedGoogle Scholar
  160. 160.
    Murtra P, Sheasby AM, Hunt SP, et al. Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 2000; 405: 180–3PubMedCrossRefGoogle Scholar
  161. 161.
    Takeuchi H, Yatsugi S, Yamaguchi T. Effect of YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT 2A receptor antagonistic activity, on a marble-burying behavior test as an obsessive-compulsive disorder model. Jpn J Pharmacol 2002; 90: 197–200PubMedCrossRefGoogle Scholar
  162. 162.
    Millan MJ, Girardon S, Mullot J, et al. Stereospecific blockade of marble-burying behaviour in mice by selective, non-peptidergic neurokininl (NK1) receptor antagonists. Neuropharmacology 2002; 42: 677–84PubMedCrossRefGoogle Scholar
  163. 163.
    Gadd CA, Murtra P, De Felipe C, et al. Neurokinin-1 receptor-expressing neurons in the amygdala modulate morphine reward and anxiety behaviors in the mouse. J Neurosci 2003; 23: 271–80Google Scholar
  164. 164.
    Enserink M. Can the placebo be the cure? Science 1999; 284: 238–40PubMedCrossRefGoogle Scholar
  165. 165.
    Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002; 63 Suppl. 11: 18–24Google Scholar
  166. 166.
    Quitkin FM, Rabkin JG, Gerald J, et al. Validity of clinical trials of antidepressants. Am J Psychiatry 2000; 157: 327–37PubMedCrossRefGoogle Scholar
  167. 167.
    Ranga K, Krishnan R. Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry 2002; 63 Suppl. 11: 25–9Google Scholar
  168. 168.
    Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 2004; 29: 385–92PubMedCrossRefGoogle Scholar
  169. 169.
    Chappell P. Effects of CP122721, a selective NK1 receptor antagonist in patients with major depression. Presented at the 42nd annual meeting of the New Clinical Drug Evaluation Unit (NCDEU); 2002 Jun 12, Boca Raton (FL), USAGoogle Scholar
  170. 170.
    Montgomery SA, Keller M, Ball W, et al. Peptide approaches in the treatment of major depression: lack of efficacy of the substance P (neurokinin 1 receptor) antagonist aprepitant. Eur Neuropsychopharmacol 2004; 14(Suppl. 3): S136–37CrossRefGoogle Scholar
  171. 171.
    Steinberg R, Alonso R, Griebel G, et al. Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function. J Pharmacol Exp Ther 2001; 299: 449–58PubMedGoogle Scholar
  172. 172.
    Ribeiro SJ, Teixeira RM, Calixto JB, et al. Tachykinin NK(3) receptor involvement in anxiety. Neuropeptides 1999; 33: 181–8PubMedCrossRefGoogle Scholar
  173. 173.
    Massi M, Panocka I, de Caro G. The psychopharmacology of tachykinin NK-3 receptors in laboratory animals. Peptides 2000; 21: 1597–609PubMedCrossRefGoogle Scholar
  174. 174.
    Holmes A, Heilig M, Rupniak NM, et al. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 2003; 24: 580–8PubMedCrossRefGoogle Scholar
  175. 175.
    Giardina GA, Gagliardi S, Martinelli M. Antagonists at the neurokinin receptors: recent patent literature. IDrugs 2003; 6: 758–72PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Department of Psychiatry and PsychotherapyUniversity of Freiburg Medical SchoolFreiburgGermany
  2. 2.Department of PharmacologyUniversity College LondonLondonUK

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